According to WHO reports, malaria is the most serious known infectious disease, with incidence of 300-600 million cases per year globally and mortablity of 3 million, particularly common among African infants and other vulnerable populations. Although existing drugs such as quinoline, chloroquine, etc have some effects on malaria, the human body will rapidly generate resistance during treatments. Nevertheless, ancient Chinese people used the Saxifragaceae herb Dichroa febrifuga (Chang Shan) to cure malaria. In 1950s, Chinese scientists extracted febrifugine from the plant and discovered its anti-malarial activity. The absolute configuration of its compound, however, was not finally determined until 1999 through chiral synthesis.
Halofuginone derivative, as an inhibitor of specific type I collagen gene expression, may play a role in many fiber cells and inhibit collagen expression synthesis in experimental fibrosis models of liver, lung, derma and uterus. The most important halofuginone derivatives are Halofuginone and Febrifugine. As Halofuginone plays a role in specific collagen transcription, it is a promising anti-hepatic fibrosis agent. In 2002, Tempostatin® (Halofuginone hydrobromide) developed by Collgard Biopharms was approved in Europe as a new orphan drug for treatment of systemic sclerosis. RU-19110 developed by a French company, Roussel Ucla, has entered clinical study.
Currently, synthesis of halofuginone derivatives generally refers to procedures developed by Japanese scientist Takeuchi Y (Chemical Communication, 2000, 1643-1644), which applies enzyme reduction to get key chiral intermediate, then obtain bromide A via a four-step reaction, and finally obtain CBZ-protected halofuginone derivative (3-)[[(3aR,7aS)-N-CBZ-2-hydroxyl-Octahydro furan and [3,2-b]2-Piperidinyl]methyl]-4(3H)-quinazolinone) through condensation (as shown in structural formula II). In his method, deprotection is performed as palladium hydroxide-catalyzed hydrogenation. The method includes 11 steps, with a total yield of 5.88%. However, side reactions will occur when using palladium hydroxide-catalyzed hydrogenation as deprotection, e.g., carbon-nitrogen double bond in the quinazolinone structure will be reduced additively to produce by-products such as C1; if quinazolinone structure contains bromine and chlorine, it is easier to be deprotected to produce by-products such as C2 and C3. Therefore, this method is not applicable to commercial production of Halofuginone.

Haruhisa K et al. also reported that palladium on carbon catalytic hydrogenation process is not applicable to some halofuginone derivatives, and acid reflux method for deprotection is not applicable to condensate (II) as hydroxyl in the condensate structure is easy to be removed (J. Med. Chem., 2006, 49, 4698). Only hydroxyl in the condensate structure firstly protected can then strong acid reflux method to be used in deprotection (U.S. Pat. No. 6,420,372).

Kobayashi S. reported a method which uses chiral formaldehyde as raw material to obtain hydroxyl-protected piperidine bromide B via synthesis, followed by condensation to obtain hydroxyl-protected condensate V, then use palladium on carbon catalytic hydrogenation and acid, respectively, to deprotect CBZ and R1 (U.S. Pat. No. 6,420,372 and J. Org. Chem., 1999, 64, 6833). The process uses expensive catalyst to synthesize hydroxyl-protected piperidine bromide B but with low yield, so the process is only applicable to lab-scale preparation of halofuginone derivative rather than commercial production.

Chinese Patent No. ZL200410045471 and Taniguchi T. et al. (Org. Lett., 2000, 2, 3193) reported that take epoxy compound C of piperidine structure as a key intermediate, condense it with quinolinone, obtain condensate V via Dess-Martin oxidation, and then obtain halofuginone derivative after deprotection by hydrogenation or acid. This method not only needs 10 steps to obtain epoxy compound 3, but also needs rare metal with a total yield of 11%. Furthermore, the application of RCM reaction and rare metal limits its commercial use.

Therefore, developing an effective and simple method to deprotect CBZ in condensate (II) is key to synthesize halofuginone via chemical methods. The present invention for the first time proposes Ni—B non-crystalline alloy as catalyst to deprotect CBZ via catalytic hydrogenation.